1. Field of the Invention
This invention relates to danazol-containing topical preparations which are markedly effective in the treatment of pelvic endometriosis and uterine adenomyosis. More particularly, it relates to intrauterine and vaginal preparations comprising a matrix base having danazol retained therein.
2. Description of the Prior Art
Endometriosis is a disease which occurs mostly in mature women and is frequently associated with infertility. According to the site of the focus, it is broadly divided into pelvic endometriosis (external endometriosis) and uterine adenomyosis (internal endometriosis).
Danazol is a drug which is highly estimated and widely used as an oral remedy for endometriosis ("Gekkan Yakuji", Vol. 25, No. 4, p. 691, 1983), but its effectiveness as a topical remedy has been unknown not only in Japan but also throughout the world. This seems to be due to the fact that two theories are being widely supported in connection with the mode of action of orally administered danazol. One of them is the worldwide established theory that orally administered danazol suppresses the function of the hypothalamo-hypophysial system to decrease the secretion of follicle-stimulating hormone (FSH) and luteinizing hormone (LH), resulting in decreased secretion of estrogens by the ovary and eventual shrinkage of endometriosis tissue (Fertility and Sterility, Vol. 29, p. 637, 1978). In other words, this theory insists that oral administration of danazol is the so-called pseudomenopausal therapy in which the functions of the ovary are suppressed completely. The other is a corrected theory which accepts the foregoing established theory in principle, but admits the presence of an appreciable direct effect on endometriosis cells (American Journal of Obstetrics and Gynecology, Vol. 140, p. 62, 1981).
Meanwhile, almost all women suffering from endometriosis become infertile. As pelvic endometriosis extends, menstrual pain appears and further aggravation results in a complaint of non-menstrual pain in the loins or lower abdomen. In cases of uterine adenomyosis, many patients complain of menstrual pain and hypermenorrhea in addition to infertility. Thus, most patients with endometriosis consult a doctor for medical advice about their infertility. It is only a few that complain chiefly of menstrual pain and have no desire for pregnancy in the future. In other words, the desire of most patients is the success of pregnancy, and the treatment of menstrual or non-menstrual pain is nothing but a secondary desire.
However, oral administration of danazol is ineffective in most cases of uterine adenomyosis. On the other hand, orally administered danazol is considerably effective for pelvic endometriosis, but has the following disadvantages. (1) The patient is utterly unable to conceive during and soon after the treatment because ovulation is suppressed. (2) The pregnancy rate after discontinuance of the treatment is low. (3) It is not rare that a recurrence of endometriosis occurs several months after discontinuance of the treatment.
As a result of intensive investigations made in view of these circumstances, the present inventor has unexpectedly found that (1) intrauterine application of danazol has a marked effect on uterine adenomyosis for which its oral administration has been virtually ineffective; (2) vaginal application of danazol does not suppress ovulation even during treatment and the patient may become pregnant even during treatment; (3) a high pregnancy rate is achieved as contrasted with oral administration; (4) prolonged vaginal application of danazol can prevent the recurrence of endometriosis which is often encountered after discontinuance of its oral administration; and (5) topical application of danazol is not associated with such side effects as are often encountered in its oral administration, including a weight gain, an aggravation of acne, a (transient) hepatic functional disorder and the like. Thus, the present inventor has first demonstrated the incorrectness of the conventionally established idea that the effect of danazol on endometriosis is produced by suppressing the endocrine functions of the hypothalamus-hypophysis-ovary system perfectly. The present invention has been completed on the basis of these findings.